FUBL-3/FUBP1 mediates mitochondrial stress-induced chromatin remodeling and longevity.

Abstract

Mitochondrial stress activates nuclear transcriptional programs to restore homeostasis and promote longevity; yet, the nuclear effector that directly reshapes chromatin during stress remains unclear. Through a forward genetic screen in <i>Caenorhabditis elegans</i>, we identify FUBL-3, the homolog of human far-upstream elements binding protein 1 (FUBP1), as a conserved regulator that couples mitochondrial stress to chromatin remodeling. FUBL-3 translocates to intestinal nuclei upon stress, where it drives nucleosome remodeling and deacetylase-dependent chromatin condensation and activates mitochondrial unfolded protein response (UPR^mt). Loss of <i>fubl-3</i> disrupts chromatin compaction and abolishes stress-induced lifespan extension, while its overexpression is sufficient to restructure chromatin, trigger UPR^mt, and extend lifespan. Notably, human FUBP1 rescues <i>fubl-3</i> mutants in worms and mediates chromatin remodeling in mammalian cells under mitochondrial stress. FUBP1 binds promoters of proteostasis and mitochondrial quality control genes, supporting its role in nuclear adaptation. Our study identifies FUBL-3/FUBP1 as a conserved mitochondrial-to-nuclear communicator that reprograms chromatin architecture to promote stress resilience and healthy aging.